title: Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy.
abstract: Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution. It usually presents in the sixth decade with progressive swallowing difficulties (dysphagia), eyelid drooping (ptosis) and proximal limb weakness. Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark. We isolated the poly(A) binding protein 2 gene (PABP2) from a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manuscript submitted). A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD. Thus the (GCG)7 allele is an example of a polymorphism which can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.
authors.affiliation: Centre for Research in Neurosciences, McGill University, Montreal General Hospital, Québec, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Brais
authors.forename: J P
authors.initials: JP
authors.lastname: Bouchard
authors.forename: Y G
authors.initials: YG
authors.lastname: Xie
authors.forename: D L
authors.initials: DL
authors.lastname: Rochefort
authors.forename: N
authors.initials: N
authors.lastname: Chrétien
authors.forename: F M
authors.initials: FM
authors.lastname: Tomé
authors.forename: R G
authors.initials: RG
authors.lastname: Lafrenière
authors.forename: J M
authors.initials: JM
authors.lastname: Rommens
authors.forename: E
authors.initials: E
authors.lastname: Uyama
authors.forename: O
authors.initials: O
authors.lastname: Nohira
authors.forename: S
authors.initials: S
authors.lastname: Blumen
authors.forename: A D
authors.initials: AD
authors.lastname: Korczyn
authors.forename: P
authors.initials: P
authors.lastname: Heutink
authors.forename: J
authors.initials: J
authors.lastname: Mathieu
authors.forename: A
authors.initials: A
authors.lastname: Duranceau
authors.forename: F
authors.initials: F
authors.lastname: Codère
authors.forename: M
authors.initials: M
authors.lastname: Fardeau
authors.forename: G A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: A D
authors.initials: AD
authors.lastname: Korcyn
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D002170:Canada; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14; D003001:Cloning, Molecular; D005260:Female; D005602:France / Q000208:ethnology; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000235:genetics*; D010375:Pedigree; D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins / Q000235:genetics*; D018911:Trinucleotide Repeats; D044465:White People
chemical_list: D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins